Organic Chemistry Reactions Summary Cheat Sheet, Cheat Sheet of Organic Chemistry

Download Organic Chemistry Reactions Summary Cheat Sheet and more Cheat Sheet Organic Chemistry in PDF only on Docsity! Typical First Year Organic Reactions 1 y:\files\classes\Organic Chemistry Tool Chest\Reactions Lists\Org rxns summary, SN-E, C=O, epoxides chem, with mechs.doc Organic Reactions Summary For Use as a Study Guide Typical First Year Organic Reactions 2 Important acid/base reactions used in the examples below. Write out every one of these easy mechanisms. OHNa thiolates are good nucleophiles, SN2 > E2 at Me, 1 o and 2o RX, and strong bases, E2 > SN2 at 3oRX. thiolates sodium hydroxide R H2 C S H thiols R H2 C S Na Keq = Ka(RSH) Ka(H2O) 10-8 10-16 = 10+8Keq = n-BuLi LDA is a very strong base that is also very sterically hindered, it always acts as a base in our course. LDA = lithium diisopropylamidediisopropylamine Li Keq = Ka(HNR2) Ka(H-C4H9) 10-37 10-50 = 10+13Keq = N H n-butyl lithium N Typical First Year Organic Reactions 5 SN2 versus E2 choices at 2 oRX. At secondary RX (X= OTs, I, Br, Cl) SN2 and E2 products are in close competition with each other. Anions whose conjugate acids have higher pKa’s (stronger bases have weaker acids) generally produce more E2 relative to SN2. The examples that we will emphasize at 2oRX centers are carboxlyates (SN2 > E2) vs hydroxide and alkoxides (E2 > SN2), and cyanide (SN2 > E2) vs terminal acetylides (E2 > SN2), azide (SN2 > E2) vs dialkylamides (E2 > SN2) and metal hydrides (SN2 > E2) vs simple hydride (E2 > SN2). Higher basicity and steric hindrance in either RX or the electron pair donor also favors E2 > SN2. The following examples show similar looking base/nucleophiles (used in our course) that react differently with 2oRX structures. (They all react by SN2 at methyl and 1 oRX and they all react by E2 at 3oRX.) It is the reactions at 2o RX centers that are ambiguous. 2o RX structures are the most ambiguous. Less basic, so SN2 > E2. More basic, so E2 > SN2. CN CCR pKa of conjugate acid = 9 pKa of conjugate acid = 25 pKa of conjugate acid = 5 pKa of conjugate acid = 16-19 R C O O OH OR cyanide terminal acetylides carboxylates hydroxide and alkoxides More basic, so E2 > SN2.Less basic, so SN2 > E2. Less basic, so SN2 > E2. More basic, so E2 > SN2. pKa of conjugate acid = 5 pKa of conjugate acid = 37 pKa of conjugate acid = ? pKa of conjugate acid = 37azide dialkyl amides sodium borohydride lithium aluminum hydride hydrides More basic, so E2 > SN2.Less basic, so SN2 > E2. H B H H H H Al H H H H LiNa H Na K N N N N R R Na Na Typical First Year Organic Reactions 6 1. Making RBr from alkane and alkene hydrocarbons and alcohols a. RBr from alkanes - mechanism using Br2 / h for free radical substitution of alkane sp3 C-H bonds to form sp3 C-Br bonds at the weakest C-H bond. H3C H2 C CH3 H3C CH CH3 Br BrBr overall reaction h BrH 1. initiation BrBr h BrBr H = 46 kcal/mole weakest bond ruptures first 2b propagation H3C C CH3 H BrBr H3C C CH3 H Br Br H = -22 kcal/mole (overall) BE = +46 kcal/mole BE = -68 kcal/mole 2a propagation H3C C CH3 H H Br BrH H3C C CH3 H H = +7 kcal/mole (overall) BE = +95 kcal/mole BE = -88 kcal/mole H = -15 both steps 3. termination = combination of two free radicals - relatively rare because free radicals are at low concentrations Br H3C C CH3 H H3C C CH3 H Br H3C C CH3 H CH3 C H3C H CH CH3 H3C CH CH3 CH3 H = -68 kcal/mole H = -80 kcal/mole very minor product Example reactions Br Br2 / h CH4 Br2 / h BrH3C achiral achiral Br enantiomers (R and S)Br2 / h Br achiral Br2 / h can do E2 twice, to make alkynes 2 Br2 / h Br Br Typical First Year Organic Reactions 7 Br allylic substitutionBr2 / h b. RBr from alkenes (anti-Markovnikov addition of HBr using free radical chemistry): mechanism using HBr / ROOR / h for free radical addition to alkane pi bonds (anti-Markovnikov addition = Br adds to less substituted position to form most stable free radical intermediate, and then H adds to more substituted position) H3C H2 C C H2 Br H3C H C CH2 HBr R2O2 (cat.) h overall reaction 1. initiation (two steps) R O O R h R O O R BrH R O R O H Br H = 40 kcal/mole H = -23 kcal/mole BE = +88 kcal/mole BE = -111 kcal/mole (cat.) reagent 2a propagation H3C H C CH2 Br H3C C C H2 Br H H = -5 kcal/mole BE = +63 kcal/mole BE = -68 kcal/mole H = -15 both steps (2a + 2b) 2b propagation H3C C C H2 Br H BrH H3C H2 C C H2 Br Br H = -10 kcal/mole BE = +88 kcal/mole BE = -98 kcal/mole 3. termination = combination of two free radicals - relatively rare because free radicals are at low concentrations Br H3C C C H2 H Br C H2 C CH3 H C H2 C H3C H CH CH3 H2 C CH C H2 CH3 H = -68 kcal/mole H = -80 kcal/mole very minor products H3C C C H2 Br H Br Br Br Br Br Example reactions H-Br / h ROOR (cat.) Br achiral Br2 / h ROOR (cat.) Br achiral Typical First Year Organic Reactions 10 OH HBr Br R S achiral SN1 rearrangement OH Cl SN2 or SN1 HCl achiral CH C CH3 HBr H3C CH3 C H2 C CH3 H3C CH3 CH CH CH3 Br H3C CH3 BrHO H major achiral rearrangement minor R/S enantiomers HBr OH CH3 Br CH3 CH3 Br achiral (cis and trans) ii. mechanism using PBr3 : SN2 at methyl and 1 o ROH; SN1 at 2 o and 3o ROH, with possibility of rearrangements H3C H2 C C H2 O CH C CH3 H3C CH3 C H2 C CH3 H3C CH3 O H H H3C H2 C C H2 O PBr2 H Br H3C H2 C C H2 Br H O PBr2 H CH C CH3 H3C CH3 O HH PBr2 C C CH3 H3C CH3 H H Br CH C CH3 H3C CH3 Br H CH C CH3 H3C CH3 H Br Br C H2 C CH3 H3C CH3 Br achiral Br P Br Br Br P Br Br rearrangement SN2 SN1 S R adds to both faces Typical First Year Organic Reactions 11 Example reactions OH I SN2 P/I2 = PI3 OH Cl SN2 R/S enantiomers PCl3 OH Br SN1 achiral PBr3 OH Br R S achiral SN1 rearrangement PBr3 OH Cl SN2 or SN1 achiral PCl3 CH C CH3 H3C CH3 C H2 C CH3 H3C CH3 CH CH CH3 Br H3C CH3 BrHO H major achiral rearrangement minor R/S enantiomers PBr3 SN1 OH CH3 Br CH3 CH3 Br achiral (cis and trans) PBr3 SN1 iii. mechanism using SOBr2 SN2 at methyl and 1o ROH; SN1 at 2o and 3o ROH, with possibility of rearrangements H3C H2 C C H2 O H H3C H2 C C H2 O H S Br Br S Br O O Br Br H3C H2 C C H2 O H S O Br SN2 H3C H2 C C H2 Br O H S O BrO H S O BrO S O Br H Typical First Year Organic Reactions 12 CH C CH3 H3C CH3 C H2 C CH3 H3C CH3 O HH CH C CH3 H3C CH3 O HH S C C CH3 H3C CH3 H H Br CH C CH3 H3C CH3 Br H CH C CH3 H3C CH3 H Br Br C H2 C CH3 H3C CH3 Br achiral rearrangement S R adds to both faces Br S Br O O Br Br CH C CH3 H3C CH3 O HH S O Br O H S O Br O H S O Br O S O Br H SN1 Example reactions OH ClSOCl2 SN2 OH Cl SN2 R/S enantiomers SOCl2 OH Br SN1 achiral SOBr2 OH Br R S achiral SN1 rearrangement SOBr2 OH Br SN2 or SN1 achiral SOBr2 CH C CH3 H3C CH3 C H2 C CH3 H3C CH3 CH CH CH3 Br H3C CH3 BrHO H major achiral rearrangement minor R/S enantiomers SN1 SOBr2 Typical First Year Organic Reactions 15 BrR S NaOH S E2 > SN2 Br OH achiral SN2 NaOH b. mechanisms using NaOCH3, SN2 at methyl and 1o RBr; E2 > SN2 at 2o and only E2 at 3o RBr, H3C O C H H H Br CO H H H H3C Br SN2 H3C O C D H CH2 Br CO D H H2C H3C Br SN2 H3C CH3 H3C O C H C H2 Br CO H CH3 H2C H3C BrE2 > SN2 CH3 H CHa CH3 Hb SN2 E2 (-CH2-H) E2 (-CHa-H) E2 (-CHb-H) R S S S R Example reactions Br O NaOCH3 SN2 inversion of configuration CH3 Br O R S E2 > SN2 CH3 NaOCH3 Br E2NaOCH3 BrR S S E2 > SN2NaOCH3 Br O achiral SN2 CH3 NaOCH3 Typical First Year Organic Reactions 16 c. mechanisms using NaO2CCH3, sodium carboxylates, SN2 at methyl 1o and 2o RBr; and only E2 at 3o RBr Ester synthesis (can hydrolyze with NaOH (base) to ROH and RCO2H, providing an alternate approach to secondary alcohols). C O C H H H Br CO H H H C Br SN2 C D H CH2 Br CO D H H2C C Br SN2 H3C CH3 C H C H2 Br CO H CH3 H2C C Br SN2 > E2 CH3 H CHa CH3 Hb R O H3C CH3 O C O O H3C C O O H3C O H3C O H3C NaOH NaOH CO D H H2C H CH3 CO H CH3 H2C H CH3 C O O H3C H H O S S S R R Example reactions BrH3C C R O O Na R C O CH3 O SN2 Br C R O O Na O C O R SN2 > E2 achiral OH O C O R acyl substitution NaOH / H2O 2o alcohol Br C R O O Na E2 Br O C RC R O O Na O SN2 allylic and benzylic, very fast SN2 reactions Typical First Year Organic Reactions 17 Br no reaction C R O O Na d. mechanism using potassium t-butoxide, KOC(CH3)3, SN2 at methyl and E2 at 1o, 2o and 3o RBr, C H H H Br CO H H H H3C Br SN2 C D H C Br Br E2 C O C H C H2 Br BrE2 H CHa CH3 Hb E2 (-CH2-H) E2 (-CHa-H) E2 (-CHb-H) R Z H3C H3C CH3 C O H3C H3C CH3 C O H3C H3C CH3 Ha CH3 Hb C C CH3 D H Hb E C C Ha D H H3C S Example reactions Br KOC(CH3)3 E2 > SN2 anti elimination Br R E2KOC(CH3)3 Br E2KOC(CH3)3 BrR S S KOC(CH3)3 E2 Br O SN2 no other option C H3C CH3 CH3KOC(CH3)3 e. mechanism using NaSH, SN2 at methyl, 1o and 2o RBr and only E2 at 3o RBr, Typical First Year Organic Reactions 20 g. mechanism using NaCN, SN2 at methyl, 1o and 2o RBr and only E2 at 3o RBr, N C C H H H Br CC H H H Br SN2 C D H CH2 Br Br SN2 H3C C H C H2 Br BrH CHa CH3 Hb R SN2S N C N C N CC D H H2C N CH3 CC H CH3 H2C N CH3 R S Example reactions Br CNaCN SN2 inversion of configurationN Br C R S SN2 NaCN N Br E2NaCN BrR S CS S SN2 NaCN N Br C achiral SN2 NaCN N Typical First Year Organic Reactions 21 h. mechanism using NaCC-R, SN2 at methyl, 1o and 2o RBr and only E2 at 3o RBr, C C C H H H Br CC H H H Br SN2 C D H CH2 Br Br SN2 H3C R C CC D H H2C C CH3 R C C R C C R R R C H C H2 Br Br E2 > SN2 H CHa CH3 Hb SN2 E2 (-CH2-H) E2 (-CHa-H) E2 (-CHb-H) CC D CH3 H2C C CH3 R S S R Example reactions Br SN2 inversion of configuration NaCC-R R Br R NaCC-R E2 > SN2 Br E2NaCC-R BrR S S E2 > SN2NaCC-R Br C achiral SN2 CNaCC-R R Typical First Year Organic Reactions 22 i. mechanism using 1. NaN3, SN2 at methyl, 1o and 2o RBr and only E2 at 3o RBr 2. LiAlH4 3. Workup, makes 1o amines (RNH2) C H H H Br CN H H H SN2 C D H CH2 Br SN2 H3C C H C H2 Br H CHa CH3 Hb R SN2 S C D H H2C CH3 C H CH3 H2C CH3 R N N N N N N N N N N N N N N N N N Al H HH H SN2 Al H HH H SN2 Al H HH H SN2 Wk Wk Wk CH2N H H H C D H H2C CH3 H2N C H CH3 H2C CH3 H2N Br Br Br N N N N N N S S R Example reactions SN2 twiceBr NH2 1. NaN3 2. LiAlH4 3. workup Br NH2 R S SN2 1. NaN3 2. LiAlH4 3. workup Br E2 1. NaN3 2. LiAlH4 3. workup BrR S NH2S S SN2 1. NaN3 2. LiAlH4 3. workup Br NH2 achiral SN2 1. NaN3 2. LiAlH4 3. workup Typical First Year Organic Reactions 25 l. mechanism using ester enolates, SN2 at methyl, 1o and 2o RBr and only E2 at 3o RBr, C H H H Br CH2C H H H SN2 C D H CH2 Br SN2 H3C C H C H2 Br H CHa CH3 Hb R SN2 S C D H H2C CH3 C H CH3 H2C CH3 R RO C CH2 O H2C H2C RO C CH2 O RO C CH2 O CRO O CRO O CRO O -78oC LDARO C C H2 O H R N R Li -78oC LDARO C C H2 O H R N R Li -78oC LDARO C C H2 O H R N R Li S Example reactions SN2 inversion of configuration 1. LDA, -78oC 2. Br O O R O O R Br R S SN2 1. LDA, -78oC 2. O O R O Br E2 1. LDA, -78oC 2. O O R BrR S S S SN2 1. LDA, -78oC 2. O O R O O R Br achiral SN2 1. LDA, -78oC 2. O O R O O R Typical First Year Organic Reactions 26 m. mechanism using acid dianion enolates, SN2 at methyl, 1o and 2o RBr and only E2 at 3o RBr, C H H H Br CH2C H H H SN2 C D H CH2 Br SN2 H3C C H C H2 Br H CHa CH3 Hb R SN2 S C D H H2C CH3 C H CH3 H2C CH3 R O C CH2 O H2C H2C O C CH2 O O C CH2 O CHO O CHO O CHO O -78oC LDAO C C H2 O H R N R Li -78oC LDAO C C H2 O H R N R Li -78oC LDAO C C H2 O H R N R Li 3. Wk 3. Wk 3. Wk S Example reactions 1. 2 eqs. LDA 2. SN2 O O H 3. workup Br O O H Br R S SN2 1. 2 eqs. LDA 2. 3. workup O O H O OH Br E2 1. 2 eqs. LDA 2. 3. workup O O H 1. 2 eqs. LDA 2. BrR S S S SN2O O H O O H 3. workup Br achiral SN2 1. 2 eqs. LDA 2. 3. workup O O H O OH Typical First Year Organic Reactions 27 n. mechanism using nitrile enolates, SN2 at methyl, 1o and 2o RBr and only E2 at 3o RBr, C H H H Br CH2C H H H SN2 C D H CH2 Br SN2 H3C C H C H2 Br H CHa CH3 Hb R SN2 S C D H H2C CH3 C H CH3 H2C CH3 R H2C H2C C C C -78oC LDA C C H2 H R N R Li -78oC LDA R N R Li -78oC LDA R N R Li N C C H2 H N C C H2 H N C CH2 N C CH2 N C CH2 N Li Li Li N N N S Example reactions 1. 2 eqs. LDA 2. 3. workup Br CH3 C SN2 inversion of configuration N C N Br R S SN2CH3 C N 1. 2 eqs. LDA 2. 3. workup C N Br E2 1. 2 eqs. LDA 2. 3. workup CH3 C N BrR S S S SN2 1. 2 eqs. LDA 2. 3. workup CH3 C N C N Br achiral SN2 1. 2 eqs. LDA 2. 3. workup CH3 C N C N Typical First Year Organic Reactions 30 p. mechanism using LiAlH4 or NaBH4 (and deuterides), SN2 at methyl, 1o and 2o RBr and only E2 at 3o RBr, C H H H Br CD H H H SN2 C D H CH2 Br SN2 H3C C H C H2 Br H CHa CH3 Hb R SN2 S C D H H2C CH3 C H CH3 H2C CH3 R H D Li Li Al D DD D Al D DD D B H HH H Na becomes achiral Example reactions Br DLiAlD4 SN2 inversion of configuration Br D R S SN2 NaBD4 Br E2LiAlD4 BrR S DS S SN2 NaBD4 Br D achiral SN2 LiAlD4 Typical First Year Organic Reactions 31 q. mechanism using diphenylsulfide to make diphenylsulfonium salt, SN2 at methyl, 1o and 2o RBr and only E2 at 3o RBr, used to make a diphenylsulfonium ylids, which are used to make epoxides with aldehydes and ketones. Br Ph S C Ph Br H H H Ph S C Ph H H H CH2 Li Ph S CH2 Ph C H H O Ph S C H2 Ph H2 C O H2C CH2 OPh S Phsimilar mechanisms Ph = phenyl 1. n-BuLi 2. H2C=O ylid salt C H H CH2 Br SN2 H3C R C H H H2C CH3 SS Ph Ph Ph Ph Br 1. n-BuLi 2. H2C=O CH2 HC H2 C H3C O ylid salt CH2 Li Ph S C Ph C H H O H2C CH3 H Ph S CH Ph H2 C O CH2H3C Ph S Ph C H C H2 Br H CHa CH3 Hb S R S Ph Ph SN2 C H CH3 H2C CH3 S Ph Ph Br 1. n-BuLi 2. H2C=O CH2 C H2 C H3C O ylid salt CH2 Li Ph S C Ph C H H O H2C CH3 CH3 Ph S C Ph H2 C O CH2H3C Ph S Ph H3C H3C Example reactions Ph S Ph SN2 inversion of configuration 1. Br 2. n-BuLi 3. H2C=O O Br R S SN2 1. 2. n-BuLi 3. H2C=O Ph S Ph O Typical First Year Organic Reactions 32 Br E2 1. 2. n-BuLi 3. H2C=O Ph S Ph BrR S S SN2 1. 2. n-BuLi 3. H2C=O Ph S Ph O Br achiral SN2 1. 2. n-BuLi 3. H2C=O Ph S Ph O r. mechanism using triphenylphosphine to make triphenylphosphonium salt, SN2 at methyl, 1o and 2o RBr and only E2 at 3o RBr, used to make a triphenylphosphonium ylid to make Z and E alkenes with aldehydes and ketones. Br C Br H CH3 H CH2 Li Ph P C Ph C H CH3 O Ph P C Ph C Ph = phenyl 1. n-BuLi 2. H2C=O ylid salt SN2 CP H CH3 H P Ph Ph Ph Ph Ph Ph CH3 H Ph O Ph CH3 CH3 H H Ph P C Ph C O Ph CH3 CH3 H H P Ph Ph Ph O C C H CH3 H CH3 Z alkenes oxaphosphatane betaine Br C Br H3C CH2 H CH2 Li Ph P C Ph C H CH3 O Ph P C Ph C Ph = phenyl 1. n-BuLi 2. H2C=O ylid salt SN2 CP H CH2 CH3 P Ph Ph Ph Ph Ph Ph CH2 CH3 Ph O Ph CH2 CH3 H3C H Ph P C Ph C O Ph CH2 CH3 H3C H P Ph Ph Ph O C C H3C CH2 H CH3 Z alkenes oxaphosphatane betaineH3C CH3 H3C H3CH3C H3C Typical First Year Organic Reactions 35 b. RX compounds with alcohols. SN1 conditions form carbocations with possible rearrangements. Ether synthesis is the major product with E1 as minor product (unless reaction is run at high temperature). Br SN1 O O CH3 H top = bottom O H CH3 OH2 CH3 CH C CH3 H3C CH3 C H2 C CH3 H3C CH3 Br H O H R C C CH3 H3C CH3 H sp2 = flat H rearrangement top bottom CH C CH3 H3C CH3 O H CH C CH3 H3C CH3 H O S (top) R (bottom) C H2 C CH3 H3C CH3 O achiral SN1 R H R H CH C CH3 H3C CH3 O H CH C CH3 H3C CH3 H O S (top) R (bottom) RR R HC H2 C CH3 H3C CH3 O R O H R OH R O H R O H R Example reactions BrH3C OH no reaction diastereomers top & bottom achiralBr O SN1 > E1 OH Br O SN1 > E1 top = bottom OH Br SN1OOH Br no reactionOH Typical First Year Organic Reactions 36 c. RX compounds with liquid carboxylic acids. SN1 conditions form carbocations with possible rearrangements. Ester synthesis is the major product with E1 as minor product. Br SN1 top = bottom O CH C CH3 H3C CH3 C H2 C CH3 H3C CH3 Br H O C C CH3 H3C CH3 H sp2 = flat H rearrangement top bottom CH C CH3 H3C CH3 O H CH C CH3 H3C CH3 H O S (top) R (bottom) C H2 C CH3 H3C CH3 O achiral SN1 CH C CH3 H3C CH3 O H CH C CH3 H3C CH3 H O S (top) R (bottom) C H2 C CH3 H3C CH3 O HO O HO O HO O H O H O HO O O OO H O OH O HO O O OH H O O Typical First Year Organic Reactions 37 d. Oxidation of ROH with: CrO3 / pyridine (PCC). Synthesis of aldehydes or ketones. H3C C H2 C H O H H Cr O OO H3C C H2 C H O H H Cr O O O H3C C H2 C H O H Cr O O O N N H N H3C C H2 C H O Cr O O ON H PCC = pyridinium chlorochromate oxidation of primary alcohol to an aldehyde (no water to hydrate the carbonyl group) primary alcohols aldehydes E2 OH O CrO3 / pyridine (PCC) H oxidation OH O CrO3 / pyridine (PCC) oxidation OH CrO3 / pyridine (PCC) no reaction OH OCrO3 / pyridine (PCC) oxidation OH H CrO3 / pyridine (PCC) oxidation O Typical First Year Organic Reactions 40 OH no reactionDMSO / oxalyl chloride (Swern) OH O oxidation DMSO / oxalyl chloride (Swern) OH H oxidation O DMSO / oxalyl chloride (Swern) e. RCO2H with thionyl chloride. Synthesis of esters. Amides, thioesters and anhydrides (Need to make RCOCl with SOCl2 + acid.) There are a variety of approaches you could propose for this transformation. C R O O H C R O O H S O Cl Cl resonance C R O O H S O Cl Cl C R O O H S O Cl Cl Base C R O O S O Cl Cl BaseH C R O O S Cl O CR OCR O resonance C R Cl O acylium ion S Cl O Cl O S O Cl Cl resonance O R O R H Cl O Cl O H O Cl H O O O R R There are many variations of ROH and RCO2H joined together by oxygen. ester synthesis from acid chloride and alcohols R O H R O H H Typical First Year Organic Reactions 41 N R N R H Cl O Cl O N O N O R RThere are many variations of RNH2 or R2NH and RCO2H joined together by nitrogen. H H H H H H amide synthesis from acid chloride and amines R H2N R H3N Cl Typical First Year Organic Reactions 42 f. ROH with acid chlorides. Synthesis of esters. (Need to make RCOCl with SOCl2 + acid.) OH OH R Cl O R O O acyl substitution acyl substitution R Cl O R O O OH OH OH acyl substitution acyl substitution acyl substitution R Cl O R O O R Cl O R O O R Cl O R O O g. RNH2 with acid chlorides. Synthesis of amides. (Need to make RCOCl with SOCl2 + acid.) NH2 NH2 R Cl O R N H O acyl substitution acyl substitution R Cl O R N H O NH2 acyl substitution R Cl O R N H O NH2 NH2 acyl substitution acyl substitution R Cl O R N H O R Cl O R N H O Typical First Year Organic Reactions 45 probably E2OH H2SO4 /  OH E1 H2SO4 /  OH E1 H2SO4 /  OH E1H2SO4 /  E1 H2SO4 /  OH l. Double elimination from dibromoalkanes to form alkynes and terminal acetylides used in many additional reactions (SN2 with RBr, C=O addition to aldehyses and ketones, and reaction with epoxides) BrBr H N R R Na Br H H N R R H N R R Na Na 2. workup H H2 C R X H2 C R H O H H 2. a a b SN2 2 eqs. Br2 h 3rd equivalent most stable anion in mixture b Na CH R O C R 2. b c Na 2. b d NaO O H2O HCH R O H H OH2O H HO d c Typical First Year Organic Reactions 46 The zipper reaction moves a triple bond in an unbranched linear chain to the end and allows all of the above reactions. C C R H2 C H R N R Na C C R CH2 C C R CH2 C C C R H H H R N R C C C R H H R N R H C C C R H H R N R H C C C R 2. workup H O H H Na R N R Na H H H C C C R H H R N R H C H2 C C R H j. Formation of conjugate base + addition of epoxide electrophile forms an alkynyl alcohol via SN2 reaction. O O 1. NaNR2 2. 1. NaNR2 2. O 1. NaNR2 2. O 1. NaNR2 2. OHR R R OH OH OH R Typical First Year Organic Reactions 47 Epoxide chemistry a. Epoxides with aqueous hydroxide (followed by workup = neutralization). O R O O O NaOH H2O 2. WK NaOH H2O 2. WK NaOH H2O 2. WK NaOH H2O 2. WK HO OH HO OH OH OH OH OH OH OH S S R S S S R S R diastereomers achiral chiral achiral R b. Epoxides with alcoholic alkoxide (followed by workup = neutralization). O R O O O RO / ROH 2. WK HO OR HO OR OH OR OH OR OR OH S S R S S S R S R diastereomers achiral chiral achiral RRO / ROH 2. WK RO / ROH 2. WK RO / ROH 2. WK c. Epoxides with aqueous acid. O H2SO4 / H2O (H3O +) 2. WK HO OH achiral Typical First Year Organic Reactions 50 h. Epoxides with NaBH4 (followed by workup = neutralization). NaBH41. 2. WK HO O R O chiral achiral HO No inversion, but priorities have changed. S NaBH41. 2. WK O O OH OHS S R S not stereoismers achiral R OH achiral No inversion, but priorities have changed. NaBH41. 2. WK NaBH41. 2. WK i. Epoxides with cuprates (followed by workup = neutralization). (CH3)2Cu Li cuprate reagent 1. 2. WK HO O R O O O OH OHS S R S not stereoismers achiral achiral HO OH (CH3)2Cu Li cuprate reagent 1. 2. WK (CH3)2Cu Li cuprate reagent 1. 2. WK (CH3)2Cu Li cuprate reagent 1. 2. WK CH3 CH3 achiral CH3 CH3 CH3 S S R S R Typical First Year Organic Reactions 51 j. Epoxides with lithium diisopropyl amide (LDA, followed by workup = neutralization). N R R Li lithium diisopropylamide (LDA) 1. 2. WK O R O O OHS S R S not stereoismers achiral OH achiral S R S N R R Li lithium diisopropylamide (LDA) 1. 2. WK N R R Li lithium diisopropylamide (LDA) 1. 2. WK N R R Li lithium diisopropylamide (LDA) 1. 2. WK O S R OHR Senantiomers OH OH k. Epoxides with Grignard reagents (followed by workup = neutralization). (MgBr)H3C H2 C H2C Grignard reagent 1. 2. WK HO O R O O O OH OHS S R S not stereoismers achiral achiral HO OH chiral S S R S R (MgBr)H3C H2 C H2C Grignard reagent 1. 2. WK (MgBr)H3C H2 C H2C Grignard reagent 1. 2. WK (MgBr)H3C H2 C H2C Grignard reagent 1. 2. WK R Typical First Year Organic Reactions 52 l. Epoxides with organolithium reagents (followed by workup = neutralization). LiHC H3C H3C organolithium reagent 2. WK 1. HO O R O O O OH OHSS R S not stereoismers achiral achiral HO OH chiral S R S RLiHC H3C H3C organolithium reagent 2. WK 1. LiHC H3C H3C organolithium reagent 2. WK 1. LiHC H3C H3C organolithium reagent 2. WK 1. R S m. Epoxides with conjugate base of phthalimide (followed by hydrolysis and workup = neutralization). N O O H NaOH 1. 2. epoxide 3. NaOH 4. WK HO O achiralNH2 O R O O OH OHSS R S not stereoismers achiral HO OH NH2 chiral NH2 NH2 NH2S R S R R S N O O H NaOH 1. 2. epoxide 3. NaOH 4. WK N O O H NaOH 1. 2. epoxide 3. NaOH 4. WK N O O H NaOH 1. 2. epoxide 3. NaOH 4. WK Typical First Year Organic Reactions 55 O H2NNH2 / RO / D Wolff-Kishner reduction f. Aldehydes and ketones with LiAlH4 (LAH). LiAlH41. 2. WK O H O O O LiAlH41. 2. WK LiAlH41. 2. WK LiAlH41. 2. WK OH OH OH OH OH OH achiral diastereomers chiral enantiomers R S enantiomers (R and S) achiral g. Aldehydes and ketones with NaBH4. NaBH41. 2. WK O H O O OH OH OH OH achiral diastereomers enantiomers (R and S) achiral NaBH41. 2. WK NaBH41. 2. WK O OH OH chiral enantiomers R SNaBH41. 2. WK Typical First Year Organic Reactions 56 h. Aldehydes and ketones with cyanide, cyanohydrin synthesis or conjugate addition to alpha-beta unsaturated C=O. 1. NaCN 2. acid addition O H O O O C O achiral diastereomers conjugate addition, R and S enantiomers enantiomers (R and S) 1. NaCN 2. acid addition 1. NaCN 2. acid addition 1. NaCN 2. acid addition OH Nenantiomers (R and S) HO C N OH C N C N cyanohydrins cyanohydrins cyanohydrins i. Aldehydes and ketones with terminal acetylides. Na R O H O O achiral diastereomers enantiomers (R and S) OH enantiomers (R and S) HO OH 2. WK 1. Na R 2. WK 1. Na R 2. WK 1. R R R O Na R 2. WK 1. OH R enantiomers (R and S) Typical First Year Organic Reactions 57 j. Aldehydes and ketones with LDA makes enolates (carbanion nucleophiles). N R R Li lithium diisopropylamide (LDA) O H O O O O H O O O N R R Li lithium diisopropylamide (LDA) N R R Li lithium diisopropylamide (LDA) N R R Li lithium diisopropylamide (LDA) enolate enolate enolate enolate k. Aldehydes and ketones with Grignard (Mg) reagents. O H O O O OH OH OH OH (MgBr)H3C H2 C H2C Grignard reagent 1. 2. WK (MgBr)H3C H2 C H2C Grignard reagent 1. 2. WK (MgBr)H3C H2 C H2C Grignard reagent 1. 2. WK (MgBr)H3C H2 C H2C Grignard reagent 1. 2. WK enantiomers (R & S) enantiomers (R & S) diastereomers (cis & trans) enantiomers (R & S) Typical First Year Organic Reactions 60 p. Aldehydes and ketones with ammonia + NaBH3CN = primary amine synthesis. NH31. 2. NaH3BCN 3. WK O H O NH2 NH2NH3 1. 2. NaH3BCN 3. WK q. Aldehydes and ketones primary amine + NaBH3CN = secondary amine synthesis. NH2 1. 2. NaH3BCN 3. WK O H O NH2 1. 2. NaH3BCN 3. WK HN HN r. Aldehydes and ketones secondary amine + NaBH3CN = tertiary amine synthesis. NH 1. 2. NaH3BCN 3. WK O H O N N NH 1. 2. NaH3BCN 3. WK s. Aldehydes and ketones ethylene glycol, acid, dehydration: ketal and acetal synthesis = protection). HO OHO H O H HO OH OO OO acetal = protected aldehyde ketal = protected ketone TsOH (-H2O) TsOH (-H2O) Typical First Year Organic Reactions 61 O HO OH O O ketal = protected ketone TsOH (-H2O) O HO OH O O ketal = protected ketone TsOH (-H2O) t. Aldehydes and ketones with 1. LDA 2. RX = alkylation of C=O. N R R Li lithium diisopropylamide (LDA) 1. 2. RX (R = Me, 1o, 2o) O H O O O enantiomers and diastereomers (RR, SS, RS, SR) O H R O R achiral achiral O R O R enantiomers (R and S) N R R Li lithium diisopropylamide (LDA) 1. 2. RX (R = Me, 1o, 2o) N R R Li lithium diisopropylamide (LDA) 1. 2. RX (R = Me, 1o, 2o) N R R Li lithium diisopropylamide (LDA) 1. 2. RX (R = Me, 1o, 2o) u. Aldehydes and ketones with 1. LDA 2. epoxide = alkylation of C=O. N R R Li lithium diisopropylamide (LDA) 2. epoxide 1. O O H O H OH S S Typical First Year Organic Reactions 62 O N R R Li lithium diisopropylamide (LDA) 2. epoxide 1. O O H OH S O N R R Li lithium diisopropylamide (LDA) 2. epoxide 1. O O OH S v. Aldehydes and ketones with 1. LDA 2. another C=O = addition to C=O. Forms a beta hydroxyl carbonyl, which can be dehydrated in acid or base (with heat) to an ,-unsaturated carbonyl compound. N R R Li lithium diisopropylamide (LDA) 2. carbonyl 1. O O H O O O H O O N R R Li lithium diisopropylamide (LDA) 2. carbonyl 1. O N R R Li lithium diisopropylamide (LDA) 2. carbonyl 1. O OH acid O H (-H2O) OH OH acid (-H2O) O acid (-H2O) O w. Aldehydes and ketones with mCPBA (Baeyer-Villigar oxidation) to form esters (cyclic = lactones). O O O H meta chloroperbenzoic acid (mCPBA) O H O OH aldehyde forms carboxylic acid